There is significant heterogeneity among clinically used anesthetics with respect to their vascular effects in specific organs. Our hypothesis is that anesthetic interactions with vascular endothelium alter regional blood flows via differential effects on endothelium-dependent modulation of smooth muscle tone; these alterations may account for the specific differences in regional blood flow induced by the different anesthetics. Inhibition of endothelium-derived relaxing factor (EDRF) with N(G)- monomethyl-L-arginine (NMMA) markedly increased blood pressure and systemic and regional vascular resistance in awake and in isoflurane (ISO) and halothane (HAL) anesthetized rats. These effects were reversed by L-arginine, indicating an EDRF-related mechanism. During ISO, NMMA increased blood pressure (54%) and regional resistance in kidney(156%), skin (234%), and hepatic artery (93%) to a significantly greater degree than was seen in HAL or awake groups. These results indicated ISO enhanced EDRF action while HAL did not. In addition, NMMA decreased responses to endothelium-dependent vasodilators in the rat cremaster muscle microcirculation. In cultured bovine arterial endothelial cells, we observed that halothane inhibited the increase in cytosolic calcium that was stimulated by the endothelium-dependent vasodilator bradykinin, whereas isoflurane did not. These results indicate that the endothelium exerts significant control over the peripheral vasculature in anesthetized rats and that alterations in receptor activation/coupling may be important mechanisms by which anesthetics produce their differential vascular effects. The first aim of this proposal is to determine the effects of anesthetics (halothane, enflurane, isoflurane, ketamine, desflurane) on endothelium-dependent control of vessel diameter and blood flow in the rat cremaster muscle microcirculation using the EDRF inhibitor, NMMA. The second aim is to determine the effects of the test anesthetics on signal transduction (basal and agonist-stimulated concentrations of cytosolic calcium and inositol trisphosphate) and on the subsequent release of vasodilators (prostacyclin, EDRF) from cultured endothelial cells. Understanding the mechanisms by which anesthetics modify circulatory control will allow the anesthesiologist to pharmacologically manipulate organ blood flows and/or choose agents that will benefit patients when specific organs are at risk for ischemia or cellular hypoxia.